This project uses pharmacogenetic and neurochemical techniques to evaluate genetic and environmental influences on individual differences in response to the chronic administration of drugs of abuse and to drugs proposed for the treatment of drug abuse. We have continued to examine genetic differences in response to the convulsant and epileptogenic effects of cocaine. Having previously identified genetically distinct strains of mice that differ in their response to chronic cocaine, carbamazepine (CBZ), opiates and benzodiazepines, we are now using these models to study the biochemical mechanisms underlying the effects of the long-term administration of these drugs. To this end, we have begun to examine several neurochemical systems known to be affected by these drugs. Characterization of receptor binding parameters for subtypes of opioid receptors in a number of inbred strains has revealed a genetic correlation between the number of mu and delta receptors in mouse brain. These studies are now being expanded to examine the effects of chronic treatment with opiates on opioid receptors. We have also examined changes in GABA-stimulated 36Cl-uptake following chronic treatment with benzodiazepine agonists and inverse agonists, naltrexone or cocaine and observed that there are genotypic differences in the homeostatic regulation of GABAergic function following chronic drug treatment. Continuation of our studies of the effects of carbamazepine on cocaine seizures revealed that the efficacy of CBZ for inhibiting cocaine seizures increased with decreasing plasma and brain levels of CBZ suggesting that chronic carbamazepine induces the cytochrome P450-mediated metabolism of cocaine. In another series of pharmacogenetic studies, we conducted Mendelian cross analyses to examine genetic and environmental influences on morphine analgesia and found that environmental variables were acting to modulate genetic control of the analgesic response to morphine. We have also recently begun to conduct Recombinant Inbred - Quantitative Trait Loci analyses of chronic cocaine- and opiate-mediated behaviors and biochemical parameters to identify genetic loci mediating responses to these drugs.